FDA Alert Highlights DPD Deficiency Warnings for 5-FU, Capecitabine
The Food and Drug Administration (FDA) has issued a safety alert to increase awareness of previous updates to the prescribing label for capecitabine (Xeloda®) and fluorouracil (5-FU) products related to risks associated with dihydropyrimidine dehydrogenase (DPD) deficiency.
Capecitabine and 5-FU are both nucleoside metabolic inhibitors approved for various cancers. Capecitabine is indicated for colorectal, breast, gastric, esophageal, gastroesophageal junction, and pancreatic cancers, while 5-FU is indicated intravenously for adenocarcinomas of the colon, rectum, breast, stomach, and pancreas, as well as topically for multiple actinic or solar keratoses and superficial basal cell carcinoma.
According to the safety alert, patients with specific homozygous or compound heterozygous variants in the DYPD gene are at a greater risk for toxicity. These variants lead to a deficiency of the DPD enzyme, which is responsible for breaking down more than 80% of 5-FU. As a result, exposure to capecitabine or 5-FU in these patients can lead to acute early-onset toxicity as well as other serious adverse reactions, such as mucositis, diarrhea, neutropenia, and neurotoxicity.
In response, the FDA approved various safety revisions to the capecitabine and 5-FU product labels. Specifically, a new boxed warning was added to note the risk of serious adverse reactions or death in patients with complete DPD deficiency. The warning further advises that DPYD testing be performed prior to starting capecitabine or 5-FU, unless immediate treatment is necessary. If testing shows complete DPD deficiency, treatment with these nucleoside metabolic inhibitor therapies should be avoided entirely.
The prescribing information was also updated to include a new subsection in the Dosage and Administration and Warnings and Precautions sections to reiterate the need for evaluation and testing for DPD deficiency before starting capecitabine or 5-FU. Moreover, the new labeling highlights the need for caution in those with partial DPD deficiency, emphasizing that dosages for these patients should be individualized and modified based on tolerability and intent of treatment.
The FDA recommends that all health care providers be aware of the risks of DPD deficiency and test for DPYD genetic variants prior to starting treatment, except in cases where immediate treatment is necessary. Additionally, providers should inform patients prior to treatment with capecitabine or 5-FU of the potential toxicities associated with DPD deficiency.
Adverse reactions associated with the use of capecitabine or 5-FU should be reported to the FDA's MedWatch program.
Non-melanoma skin cancer (NMSC), also referred to as keratinocyte carcinoma, primarily consists of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC).1 Combined, BCC and SCC make up nearly 95% of skin malignancies and are the most commonly diagnosed cancers in humans.2,3 The primary risk factor for developing NMSC is ultraviolet radiation from the sun or artificial sources, which cause DNA alterations, as well as production of reactive oxygen species and a reduction in cell-mediated immune responses, leading to cellular damage.4-7
The prognosis for NMSC is favorable when it is discovered early, although this varies by subtype based on the subtype's behavior and potential to metastasize.2 BCC is less prone to metastasize but can be locally aggressive and invade nearby structures, whereas SCC has a higher tendency to be aggressive and spread to regional lymph nodes.8 Untreated NMSC lesions can lead to functional impairment, pain, changes in appearance, and even death, making timely treatment important.
Surgery is the traditionally preferred treatment for most cases of NMSC, with Mohs micrographic surgery (MMS) being the gold standard for NMSC lesions that are high risk, recurrent, or located in anatomically sensitive areas.1,9 A non-surgical alternative known as image-guided superficial radiation therapy (IG-SRT) has demonstrated remarkable efficacy in the treatment of NMSC lesions and is emerging as a prominent treatment modality.10,11
Mohs Surgery: The Gold Standard
MMS, developed in the 1930s by Dr Frederic Mohs, serves as the gold standard approach for treating select NMSC lesions.8,9 As noted, MMS is the standard of care for NMSC lesions categorized as high risk, recurrent, or located in anatomically sensitive areas.1,9 The MMS technique focuses on precision and tissue preservation.8,12 The development of this procedure marked a significant advancement in the management of NMSC, as it preserves both appearance and function compared with the standard surgical technique.
Efficacy
MMS has proven to be highly efficacious based on extensive research. A comprehensive 5-year study on the outcomes of MMS showed a 99% cure rate for the treatment of primary BCCs and a 92% to 99% cure rate for the treatment of SCCs.13 MMS also has demonstrated a higher cure rate than standard excision for the management of high-risk NMSC lesions.8 The thorough approach taken during MMS reduces the likelihood of incomplete removal of the skin cancer roots.12
Safety and Cosmetic Outcomes
Overall, patients tolerate MMS well and express high satisfaction regarding cosmetic results. The minimally invasive technique used in MMS focuses on tissue preservation. The procedure is performed under local anesthesia and begins with the removal of a thin, 1- to 2-mm margin of tissue.8,12,13 The specimen is frozen, sectioned into thin slices, stained, and placed onto slides to evaluate for any remaining cancer cells under a microscope.8,13 If positive margins remain, the patient is prepped for a second stage and the procedure is repeated until margins are clear of residual cancer cells.13 Once complete clearance of margins is achieved, the Mohs surgeon typically closes the surgical site the same day with a complex linear closure, skin flap, or graft depending on the skin defect.12 After closure, the patient typically is given aftercare instructions and a follow up visit is scheduled for suture removal, if necessary. In contrast, a standard excision involves the removal of 4- to 6-mm margins down to the mid-subcutaneous adipose tissue.1,8
It is also important that patients receive clear instructions on wound care to reduce the risk for complications and promote optimal healing. Although most patients experience pleasing cosmetic results with MMS, some can have distress related to scarring, bandaging, or sutures postprocedure.14 Complications that arise after MMS include bleeding, infection, nerve damage, and reopening of the wound.11 To reduce the risk for complications, some patients are prescribed prophylactic antibiotics or asked to temporarily discontinue their anticoagulant medication for a period of time before the procedure.12
Patients with a pacemaker or implantable cardioverter defibrillator may need to turn off their cardiac device, if possible, or have the Mohs surgeon use a disposable electrocautery device to eliminate concerns related to the use of standard electrocautery.12
Patient Eligibility
Determining patient eligibility for MMS is a crucial step in ensuring procedure appropriateness and success. The American Academy of Dermatology (AAD) recommends MMS for all high-risk NMSCs.8 High-risk NMSCs may include tumors that are larger than 2 cm, invasive histologic subtypes, sites with high recurrence rates, or sites in anatomical locations where tissue preservation is required.1,13 MMS is not recommended for patients with medical comorbidities that reduce overall general health or for patients who have abnormal bleeding tendencies.10
IG-SRT: A Non-Invasive Alternative
IG-SRT was approved by the Food and Drug Administration in 2015. IG-SRT was developed to enhance the effectiveness of superficial radiation therapy (SRT),11 which previously was used by dermatologists to treat NMSC but was replaced by MMS because of the higher cure rates seen with the surgery.15 IG-SRT uses a high-resolution dermal ultrasound and Doppler features to visualize the depth, width, and overall structure of skin tumors before, during, and after treatment.15IG-SRT is a precise procedure administered by a board-certified radiation therapist.11,16
"Studies of IG-SRT report a greater than 99% local cure rate for early-stage NMSC lesions. MMS has a 5-year local control rate of 99% for BCC lesions and 92% to 99% for SCC lesions."
The technique begins with ultrasound visualization of the exact dimensions of the skin tumor.3,11 Because the ultrasound imaging allows the tumor to be visualized prior to, during, and after treatment, the provider can adjust radiation dosages, if needed, and confirm lesion response to treatment.15 A 22-MHz high-resolution dermal ultrasound is used, which allows for visualization of skin depths up to 6 mm.10 The energies of penetration range from 50 to 100 kV and are calculated by using the tumor dimensions, as well as percentage depth dose tables provided by the ultrasound device manufacturer.10,16 Treatment typically lasts 15 minutes and occurs 3 to 5 times per week for 4 to 7 weeks.11
Efficacy
The use of image-guided ultrasound has made IG-SRT a treatment that is superior to SRT and that demonstrates cure rates that are comparable to those of MMS.15 In a recent study evaluating IG-SRT for histologically proven NMSC lesions, 2897 out of 2917 lesions showed no signs of residual tumor after treatment, resulting in a 99.3% local control rate.15 Another study examined 1899 NMSC lesions undergoing IG-SRT for 7.5 weeks showed a local control rate of 99.7%.16 Data from these studies showing the high local cute rate of over 99%, which supports IG-SRT as a highly effective treatment modality for managing NMSCs.16
Safety and Cosmetic Outcomes
IG-SRT is a well-tolerated, safe procedure that yields favorable cosmetic results.10 This procedure uses precise, low-penetration kilovoltage (kV) to target superficial skin lesions, avoiding damage to healthy tissue or deeper structures.16 IG-SRT's noninvasive technique helps preserve tissue in cosmetically sensitive areas, resulting in exceptional cosmetic outcomes.15
The procedure has demonstrated a mild side effect profile. Most side effects typically are self-resolving and last for 2 to 6 weeks following treatment.11,16 Common side effects include hyperpigmentation, desquamation, erythema, and dryness, which can be controlled with over-the-counter cream or ointment.10,11,16
Patient Eligibility
IG-SRT is an attractive treatment option for patients with superficial NMSCs, as well as patients who refuse surgery or are not surgical candidates. This procedure is recommended by the AAD for patients with early-stage NMSC who do not qualify for surgery.16 It also can be beneficial for patients with NMSC lesions located in cosmetically sensitive areas.15 However, not all patients are candidates for IG-SRT because of various contraindications. These include lesions that invade bone or muscle or have a depth greater than 6 mm, a past history of radiation therapy to the same site, connective tissue disease, rheumatologic disease, or current use of chemotherapy agents that increase sensitivity to radiation.15 Both patient eligibility and contraindications should be reviewed before offering IG-SRT as an option.
Comparative Analysis
MMS and IG-SRT both demonstrate high local cure rates in the management of NMSC, with IG-SRT showing a greater than 99% local cure rate for early-stage NMSC lesions,15,16 and MMS demonstrating a 5-year local control rate of 99% for BCC lesions and 92% to 99% for SCC lesions.10 As a noninvasive approach, IG-SRT is a valuable treatment modality, especially when surgery is not preferred or is contraindicated. MMS has proven to be highly effective in this setting and currently is the gold standard treatment for most NMSC lesions. Although both procedures offer exceptional local cure rates, factors such as patient preference, patient eligibility for the procedure, and lesion characteristics should be considered when choosing a treatment method to ensure safe, favorable outcomes.
MMS with IG-SRT each have advantages and disadvantages related to safety and cosmetic outcomes. MMS is notable for preserving tissue and taking minimal margins.1 Since this is a surgical procedure, there is a risk for scarring, bleeding, and infection.11 Special consideration must be given to patients with cardiac devices, as well as those who require prophylactic antibiotics or are on certain medications, such as anticoagulants.12 However, the majority of complications can be taken care of in-office, and patients typically are happy with the cosmetic results following surgery.12,14
IG-SRT has favorable results without the need for surgical intervention. It avoids complications such as scarring, infection, and bleeding that can be seen with MMS.1,15 This is especially important in patients who have skin that is prone to scarring or keloids.16 IG-SRT also offers advantages over MMS by preserving tissue in lesions in cosmetically challenging areas, such as the scalp, where closure is difficult, or lower legs, which heal more slowly because of poor vascularization, posing a higher risk for infection.15 It is also important to note that IG-SRT does not require local anesthesia, discontinuation of medications, or prophylactic antibiotics.11
MMS is typically completed during one office visit and takes about 2 to 4 hours depending on the number of stages needed to reach tumor clearance.11 A 1-day procedure is especially important to consider for patients who live far from the office, have trouble commuting to it, or have limited time off work.
Unlike MMS, IG-SRT has the capability to treat up to 4 lesions at once.11,16 This provides a significant advantage for patients who have multiple NMSC lesions that need to be treated. IG-SRT also has a shorter office visit time of about 15 minutes but requires 3 to 5 treatments a week over the course of 4 to 7 weeks.11 While the shorter office visits sound appealing, the treatment course requires commitment from patients for multiple visits to ensure that treatment is effective.
Although MMS is the gold standard for NMSC treatment, surgery may be contraindicated in patients with certain medical conditions, such as chronic edema, bleeding abnormalities, or cardiac conditions, and IG-SRT could be used as an alternative in such cases.11,16 In addition, a patient may decline MMS due to personal preference and opt to receive IG-SRT.
IG-SRT does have limitations and cannot be used in certain scenarios. For example, lesions that are larger than 2 cm or have previously received radiation therapy are contraindicated for IG-SRT; in such cases, MMS may be a better option.15Eligibility and contraindications for MMS and IG-SRT require careful consideration on a case-by-case basis before choosing an appropriate procedure for each patient.
Conclusion
When comparing MMS to IG-SRT, preservation of function and cosmesis, along with patient preference and tumor characteristics should be considered by both the patient and provider. Both procedures are considered safe and well-tolerated, with high patient satisfaction rates. When formulating a treatment plan for a patient with NMSC, the efficacy, safety, and cosmetic outcomes, procedure details, and patient eligibility for each procedure should be considered to ensure optimal outcomes.
Tattoos and Melanoma: A Surprising Signal from a Large Population Study
by Alexander Stratigos, MD
INTRODUCTION Tattoos are increasingly common worldwide, yet their long-term health implications—particularly in relation to skin cancer—remain incompletely understood. While tattoo inks may contain potentially carcinogenic substances and induce chronic inflammatory responses in the skin, epidemiological evidence linking tattooing to melanoma has been scarce and conflicting. A new large populationbased case–control study offers timely and provocative data, challenging prevailing assumptions and opening new avenues for research.
MAIN POINTS Study design:
Population-based case–control study including 1,167 melanoma cases (in situ and invasive) and 5,835 matched controls from Utah, the US state with the highest melanoma incidence
Results: Overall tattoo exposure: Ever having a ta#oo was not associated with melanoma risk overall (OR 0.92, 95% CI 0.74–1.13), nor with invasive melanoma (OR 0.81, 95% CI 0.60–1.09).
Dose-related findings:
Individuals with ≥4 tattoo sessions had a 56% lower risk of melanoma (OR 0.44, 95% CI 0.27–0.67) and a similar reduc7on for invasive melanoma (OR 0.43,95% CI 0.24–0.80).
Those with ≥3 large tattoos showed an even stronger inverse association (overall melanoma OR 0.26, 95% CI 0.10–0.54; invasive melanoma OR 0.23, 95% CI 0.07–0.75).
Receiving the first tattoo before age 20 was associated with a reduced risk of invasive melanoma (OR 0.48, 95% CI 0.29–0.82).
Sex-specific differences:
Among men, ≥4 tattoo sessions were associated with a marked reduction in melanoma risk (overall OR 0.25, 95% CI 0.09–0.53; invasive OR 0.15, 95% CI 0.04–0.62).
Among women, associations were weaker and mostly non-significant (≥4sessions: overall OR 0.64, 95% CI 0.36–1.07).
Low-level exposure signal: A single tattoo session was associated with an increased risk of in situ melanoma, particularly in women (overall OR 1.53, 95% CI 1.16–2.00; women OR 1.90, 95% CI 1.30–2.74), suggesting possible detection or behavioral bias.
No evidence of colocalization: Fewer than 7% of tattooed melanoma cases reported a melanoma arising within 6 inches of a tattoo, arguing against a direct local carcinogenic effect.
Comment
In this large population-based case–control study, tattooing was not associated with an increased risk of melanoma. Unexpectedly, higher levels of tattoo exposure (multiple tttoo sessions or several large tattoos) were associated with a lower risk of melanoma, particularly invasive disease and more prominently among men. While these findings challenge long-standing concerns about tattoo inks and carcinogenicity, the authors emphasize that unmeasured confounding and behavioral factors may partly explain the results, and further research is needed.
McCarty RD, Trabert B, Collin LJ, et al. Ta7ooing and risk of melanoma: a populaAon-based case-control study in Utah. J Natl Cancer Inst. 2025 Dec 1;117(12):2495-2504. doi: 10.1093/jnci/djaf235. PMID: 40839395
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